EP1765295B1 - Composition à libération prolongée, procédé servant à produire celle-ci et utilisation de celle-ci - Google Patents

Composition à libération prolongée, procédé servant à produire celle-ci et utilisation de celle-ci Download PDF

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Publication number
EP1765295B1
EP1765295B1 EP05758111A EP05758111A EP1765295B1 EP 1765295 B1 EP1765295 B1 EP 1765295B1 EP 05758111 A EP05758111 A EP 05758111A EP 05758111 A EP05758111 A EP 05758111A EP 1765295 B1 EP1765295 B1 EP 1765295B1
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sustained
emulsion
molecular weight
average molecular
lactic acid
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EP1765295B2 (fr
EP1765295A1 (fr
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Tomomichi TAKEDA PHARMACEUTICAL CO. LTD. FUTO
Kei TAKEDA PHARMACEUTICAL COMPANY LIMITED MUKAI
Jiichi TAKEDA PHARMACEUTICAL COMPANY LTD. ARAI
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • A61K9/1647—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/18—Feminine contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy

Definitions

  • the present invention relates to a sustained-release composition comprising a physiologically active substance and a process for producing it and its use.
  • Microcapsules having poor spherical property are very difficult to administer due to their own non-uniform shape, which is a big problem in medical care. Specifically, in the case where a suspension for injection is produced using such microcapsules having poor spherical property, the needle penetrating property of the resulting suspension is small and results in poor aspiration of the suspension into an injection syringe in preparing for injection, and the like. In the case where the total amount of the suspension for injection can not be aspirated into an injection syringe, the prescribed amount of a drug can not be administered and as a result, the expected efficacy of the drug can not be obtained.
  • the needle is clogged in the state of being stuck into the patient's body, which becomes an extremely big problem in medical care. Moreover, if a needle having a larger diameter is used for the purpose of obviating clogging of a needle, the pain of the patient is increased.
  • microcapsules comprising removal of microcapsules having undesired shapes by putting microcapsules through a sieve having a certain size is suggested, and however, it has a disadvantage of decreased yield.
  • JP-A 60-100516 discloses a sustained-release microcapsule of a water-soluble drug which is produced by an in-water drying method and which comprises a particle containing the water-soluble drug dispersed in a matrix having an average diameter of 2 to 200 ⁇ m consisting of a lactic acid-glycolic acid copolymer whose weight-average molecular weight is about 5,000 to 200,000 and in which lactic acid is present in about 100 to 50% by weight and glycolic acid is present in about 0 to 50% by weight.
  • JP-A 62-201816 discloses a method of producing a sustained-release microcapsule, which is characterized in that the viscosity of a W/O emulsion is adjusted to about 150 to 10,000 cp when a W/O/W emulsion is prepared.
  • JP-A 62-54760 discloses a coplymer or polymer of biodegradable polyoxycarboxylic acid ester in which the content of water-soluble oxycarboxylic acid is less than 0.01 mol/100 g as calculated on the assumption that it is monobasic acid and the weight-average molecular weight is about 2,000 to 50,000, and a sustained-release microcapsule for injection comprising the polymer.
  • JP-A 61-28521 discloses a lactic acid-glycolic acid copolymer consisting of about 50 to 95% by weight of lactic acid and about 50 to 5% by weight of glycolic acid, in which the weight-average molecular weight is about 5,000 to 30,000, a catalyst is not contained, and the dispersivity (as measured by a gel permeation chromatography method) is about 1.5 to 2, and a pharmaceutical containing the copolymer as a base.
  • JP-A 06-192068 discloses a method of producing sustained-release microcapsules characterized in that the microcapsules are heated at the glass-transition temperature of a polymer or above, at which temperature the particles of microcapsules are not attached to each other.
  • JP-A 04-218528 discloses a method of purifying biodegradable aliphatic polyester which comprises dissolving biodegradable aliphatic polyester containing a low-molecular-weight polymer having a molecular weight of 1,000 or less in an organic solvent, adding water to the solution to precipitate a high-molecular substance and then removing low-molecular polymers having a molecular weight of 1,000 or less, and it discloses that 50 to 150 parts by volume of water is added to 100 parts by volume of an organic solvent.
  • WO 03/002091 discloses a sustained-release composition containing a lactic acid-glycolic acid copolymer having a ratio of weight-average molecular weight to number-average molecular weight of about 1.90 or less or a salt thereof, and a physiologically active substance, and a microsphere containing a lactic acid-glycolic acid copolymer having weight-average molecular weight of about 11,600 to about 14,000 or a salt thereof, and a LH-RH derivative or a salt thereof, and not containing gelatin.
  • the present invention provides a process for producing a sustained-release composition which has improved spherical property and/or needle penetrating property, which contains a high content of a physiologically active substance and does not contain a drug retaining substance such as gelatin, and which can maintain a stable releasing rate over a period of about one month by suppressing its initial excessive release.
  • the present inventors under the above-described circumstances, diligently studied methods of producing a sustained-release microcapsule having great spherical property and/or needle penetrating property. As a result, they found the preferable temperature range of an oil phase used for preparation of a primary emulsion, that is, a W/O emulsion, and the preferable temperature range of the primary emulsion, and furthermore fond that a microcapsule which has great spherical property and/or needle penetrating property, which contains a high content of a physiologically active substance, and which can maintain a stable releasing rate over a period of about one month by suppressing its initial excessive release can be produced by using the preferable temperature ranges. Then, the present inventors further studied on the basis of these findings, and as a result, completed the present invention.
  • the present invention provides:
  • weight-average molecular weight (Mw) and number-average molecular weight (Mn) can be measured, for example, by the GPC method (1) described below in Reference Example 1.
  • the weight-average molecular weight (Mw) is preferably about 11,500 to about 14,000 (more preferably, about 11,600 to about 14,000) as measured by the GPC method (1) described in Reference Example 1, and preferably about 12,000 to about 14,500 as measured by the GPC method (2) described in Reference Example 1.
  • amino acid and protecting group and the other abbreviations as used herein are based on abbreviations in accordance with IUPAC-IUB (Commission on Biochemical Nomenclature) or conventional abbreviations in the art. If amino acids may have the optical isomers, they are represented in the L-configuration unless otherwise specified.
  • the sustained-release composition of the present invention is a sustained-release composition which comprises (i) a physiologically active substance and (ii) a lactic acid-glycolic acid copolymer in which the weight-average molecular weight (Mw) is about 8,000 to about 11,500, the ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) is 2.3 to 3.1, and the compositional molar ratio of lactic acid to glycolic acid is 99.9/0.1 to 60/40, or a salt thereof, and which does not contain a drug retaining substance.
  • Mw weight-average molecular weight
  • Mn number-average molecular weight
  • a physiologically active substance used in the present invention includes, but not limited to, a physiologically active peptide, an antibiotic, an antitumor agent, an antipyretic, an analgesic, an anti-inflammatory drug, an antitussive and expectorant drug, a sedative, a muscle relaxant, an antiepileptic drug, an antiulcer drug, an antidepressant, an antiallergic drug, a cardiotonic, an antiarrhythmic drug, a vasodilator, a hypotensive and diuretic drug, a mellitus diabetes therapeutic drug, an antihyperlipidemic drug, an anticoagulant, a hemostatic drug, an antituberculous drug, a hormone drug, a narcotic antagonist, a bone resorption suppressant, a bone formation accelerating agent, a angiogenesis inhibitor, and the like.
  • the above-described physiologically active peptide is preferably composed of two or more amino acids and has a molecular weight of about 200 to about 80,000, preferably about 200 to about 40,000.
  • the physiologically active peptide is preferably an LHRH (luteinizing hormone-releasing hormone) agonist or an LHRH antagonist.
  • An LHRH agonist includes, for example, a peptide represented by the formula: (Pyr) Glu-R 1 -Trp-Ser-R 2 -R 3 -R 4 -Arg-Pro-R 5 (I) [wherein, R 1 represents His, Tyr, Trp or p-NH 2 -Phe; R 2 represents Tyr or Phe; R 3 represents Gly or a D-type amino acid residue which may be substituted; R 4 represents Leu, Ile or Nle; and R 6 represents Gly-NH-R 6 (wherein R 6 represents hydrogen or alkyl having or not having hydroxyl) or NH-R 7 (wherein R 7 represents hydrogen, alkyl having or not having amino or hydroxyl, or ureide (-NH-CO-NH 2 ))] or a salt thereof.
  • R 1 represents His, Tyr, Trp or p-NH 2 -Phe
  • R 2 represents Tyr or Phe
  • R 3 represents Gly or a D-type amino acid residue which may be substitute
  • the D-type amino acid residue represented by R 3 includes, for example, ⁇ -D-amino acid containing up to 9 carbon atoms (for example, D-Leu, Ile, Nle, Val, Nval, Abu, Phe, Phg, Ser, Thr, Met, Ala, Trp, ⁇ -Aibu and the like) and the like.
  • a substituent for R 3 includes, for example, tert-butyl, tert-butoxy, tert-butoxycarbonyl, methyl, dimethyl, trimethyl, 2-naphtyl, indol-3-yl, 2-methylindolyl, benzyl-imidazol-2-yl and the like.
  • alkyl represented by R 6 or R 7 is preferably, for example, C 1-4 alkyl, and the examples include methyl, ethyl, prophyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl.
  • a salt of a peptide represented by the formula (I) includes, for example, salts of acid (for example, carbonate, bicarbonate, acetate, trifluoroacetate, propionate, succinate and the like) and metal complex compounds (for example, cupper complex, zinc complex and the like).
  • a peptide represented by the formula (I) or a salt thereof a peptide represented by the formula: 5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z [wherein Y represents DLeu, DAla, DTrp, DSer(tBu), D2Nal o: DHis (ImBzl), and Z represents NH-C 2 H 5 or Gly-NH 2 ] or a salt thereof is preferred, and furthermore a peptide represented by the formula: 5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C 2 H 5 or the acetate thereof is preferred.
  • the peptide (I). or its salt can be produced by, for example, a method described in USP No. 3,853,837 , USP No. 4,008,209 , USP No. 3,972,859 , British Patent No. 1,423,083 Proceedings of the National Academy of Sciences of the United States of America, Vol.78, pp.6509-6612 (1981 ) or the like, or a similar method to that.
  • the peptide (I) is preferably any one of peptides represented by the following formulas (a)-(j) or the like, or a salt thereof.
  • the peptide (I) or its salt is more preferably leuprorelin or leuprorelin acetate.
  • leuprorelin acetate is acetate salt of leuprorelin.
  • An LHRH antagonist includes, for example, those disclosed in USP No. 4,086,219 , USP No. 4,124,577 , USP No. 4,253,997 and USP No. 4,317,815 , and a peptide represented by the formula: wherein, X represents hydrogen or tetrahydrofurylcarboxamide, Q represents hydrogen or methyl, A represents nicotinoyl or N,N'-diethylamidino, and B represents isopropyl or N,N'-diethylamidino, [hereinafter, it may be abbreviated as peptide (II)] or its salt.
  • X is preferably tetrahydrofurylcarboxamide, more preferably (2S)-tetrahydrofurylcarboxamide.
  • A is preferably nicotinoyl.
  • B is preferably isopropyl.
  • the peptide (II) has one or more species of asymmetric carbon atoms, two or more kinds of optical isomers exist.
  • the peptide (II) may be used as such optical isomers or as mixture of such optical isomers.
  • a salt of the peptide (II) may be preferably a pharmacologically acceptable salt.
  • Such a salt includes salts with inorganic acid (for example, hydrochloride, sulfate, nitrate and the like), salts with organic acid (for example, carbonate, bicarbonate, succinate, acetate, propionate, trifluoroacetate and the like) and the like.
  • a salt of the peptide (II) is more preferably a salt with organic acid (for example, carbonate, bicarbonate, succinate, acetate, propionate, trifluoroacetate and the like).
  • a salt of the peptide (II) is still more preferably a salt with acetic acid. These salts may be mono- to tri-salts.
  • the peptide (II) or its salt is preferably represented by any one of the following formulas (1)-(4):
  • the peptide (II) or its salt is more preferably represented by the above formula (1) or (2), and in particular, it is preferably the S-isomer.
  • the S-isomer of a peptide represented by the above formula (1) is abbreviated as compound A1.
  • the peptide (II) or its salt can be produced by a per se known method, for example, a method described in JP-A 3-101695 ( EP-A 413209 ), Journal of Medicinal Chemistry, vol.35, pp.3942 (1992 ) or the like, or a similar method to that.
  • a physiologically active peptide suitably used in the present invention includes further, for example, insulin, somatostatin, somatostatin derivatives (Sandostatin, see USP No. 4, 087, 390 , USP No. 4, 093, 574 , USP No. 4,100, 117 , and USP No.
  • TRH melanocyte stimulating hormone
  • TSH thyroidstimulating hormone
  • LH luteinizing hormone
  • FSH follicle-stimulating hormone
  • endorphin kyotorphin
  • interferons for example, ⁇ type, ⁇ type, ⁇ type and the like
  • interleukins for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 and the like
  • tuftsin for example, thymopoietin, thymosin, thymostimulin, thymic humoral factor (THF), facteur thymique serique (FTS) and its derivatives (see USP No. 4,229,438 ), and the other thymic factors [" Igaku no Ayumi" (Proceedings of medicine), Vol.125, No.
  • tumor necrosis factor TNF
  • colony-stimulating factor CSF
  • CSF colony-stimulating factor
  • CSF colony-stimulating factor
  • CSF colony-stimulating factor
  • CSF colony-stimulating factor
  • GCSF colony-stimulating factor
  • CSF colony-stimulating factor
  • GCSF colony-stimulating factor
  • MCSF MCSF
  • motilin dynorphin
  • bombesin neurotensin
  • cerulein bradikinin
  • urokinase asparaginase, kallikrein, substance P
  • IGF-I, IGF-II insulin-like growth factor
  • nerve growth factor NGF
  • cell growth factor EGF, TGF- ⁇ , TGF- ⁇ , PDGF, acidic FGF, basic FGF and the like
  • BMP bone morphogenetic protein
  • neurotrophic factor NT-3, NT-4, CNTF, GDNF, BDNF and the like
  • An antibiotic includes, for example, gentamicin, dibekacin, kanedomicin, lividomicin, tobramycin, amikacin, fradiomycin, sisomicin, tetracycline hydrochloride, oxytetracycline hydrochloride, rolitetracycline, doxycycline hydrochloride, ampicillin, piperacillin, ticarcillin, cephalothin, cephaloridine, cefotiam, cefsulodin, cefmenoxime, cefmetazole, cefazolin, cefotaxime, cefoperazone, ceftizoxime, moxalactam, thienamycin, sulfazecin, aztreonam and the like.
  • An antitumor agent includes, for example, bleomycin, methotrexate, actinomycin D, mitomycin C, vinblastine sulfate, vincristine sulfate, daunorubicin, adriamycin, neocarzinostatin, cytosine arabinoside, fluorouracil, tetrahydrofuryl-5-fluorouracil, krestin, picibanil, lentinan, levamisole, bestatin, azimexon, glycyrrhizin, poly I:C, poly A:U, poly ICLC and the like.
  • An antipyretic, analgesic, or anti-inflammatory agent includes, for example, salicylic acid, sulpyrine, flufenamic acid, diclofenac, indometacin, morphine, pethidine hydrochloride, levorphanol tartrate, oxymorphone and the.
  • An antitussive and expectorant drug includes, for example, ephedrine hydrochloride, methylephedrine hydrochloride, noscapine hydrochloride, codeine phosphate, dihydrocodeine phosphate, alocramid hydrochloride, clofedanol hydrochloride, picoperidamine hydrochloride, chloperastine, protokilol hydrochloride, isoproterenol hydrochloride, salbutamol sulfate, terbutaline sulfate and the like.
  • a sedative includes, for example, chlorpromadine, prochlorperazine, trifluoperazine, atropin sulfate, methylscopolamine bromide and the like.
  • a muscle relaxant includes, for example, pridinol methanesulfonate, tubocurarine chloride, pancuronium bromide and the like.
  • An antiepileptic includes, for example, phenytoin, ethosuximide, acetazolamide sodium, chlordiazepoxide and the like.
  • An antiulcer drug includes, for example, metoclopramide, histidine hydrochloride and the like.
  • An antidepressant includes imipramine, clomipramine, noxiptiline, phenelzine sulfate and the like.
  • An antiallergic drug includes, for example, diphenhydramine hydrochloride, chlorpheniramine maleate, tripelennamine hydrochloride, methdilazine hydrochloride, clemizole hydrochloride, diphenylpyraline hydrochloride, methoxyphenamine hydrochloride and the like.
  • a cardiotonic includes, for example, trans-pi-oxocamphor, theophyllol, aminophylline, etilefrine hydrochloride and the like.
  • An antiarrhythmic drug includes, for example, propranol, alprenolol, bufetolol, oxyprenolol and the like.
  • a vasodilator includes, for example, oxyfedrine hydrochloride, diltiazem, tolazoline hydrochloride, hexobendine, bamethan sulfate and the like.
  • a hypotensive and diuretic drug includes, for example, hexamethonium bromide, pentolinium, mecamylamine hydrochloride, ecarazine hydrochloride, clonidine and the like.
  • a mellitus diabetes therapeutic drug includes, for example, glymidine sodium, glipizide, phenformin hydrochloride, buformin hydrochloride, metformin and the like.
  • An antihyperlipidemic drug includes, for example, pravastatin sodium, simvastatin, clinofibrate, clofibrate, simfibrate, bezafibrate and the like.
  • An anticoagulant includes, for example, heparin sodium and the like.
  • a hemostatic drug includes, for example, thromboplastin, thrombin, menadione sodium hydrogen sulfite, acetomenaphthone, e-aminocaproic acid, tranexamic acid, carbazochrome sodium sulfonate, adrenochrome monoaminoguanidine methanesulfonate and the like.
  • An antituberculous drug includes, for example, isoniazid, ethambutol, para-aminosalicylic acid and the like.
  • a hormone preparation includes, for example, prednisolone, prednisolone sodium phosphate, dexamethasone sodium sulfate, betamethasone sodium phosphate, hexestrol phosphate, hexestrol acetate, methimazole and the like.
  • a narcotic antagonist includes, for example, levallorphan tartrate, nalorphine hydrochloride, naloxone hydrochloride and the like.
  • a bone resorption suppressant includes, for example, ipriflavone, alendronate, risedronate and the like.
  • a bone formation accelerating agent includes, for example, (2R,4S)-(-)-N-[4-(diethoxyphosphorylmethyl)phenyl]-1,2,4,5-tetrahydro-4-methyl-7,8-methylenedioxy-5-oxo-3-benzothiepin-2-carboxamide, 2-(3-pyridyl)-ethane-1-,1-diphosphonic acid, laroxifene and the like, in addition to polypeptides such as BMP, PTH, TGF- ⁇ , and IGF-1.
  • An angiogenesis inhibitor includes, for example, antiangiogenic steroid [see Science, Vol.221, pp.719 (1983 )], fumagillin (see European Patent Publication No. 325199 ), fumagillol derivatives (see European Patent Publication No. 357061 , European Patent Publication No. 359036 , European Patent Publication No. 386667 , and European Patent Publication No. 415294 ), batimastat and the like.
  • the physiologically active substance may be used as it is or in the form of a pharmacologically acceptable salt.
  • the physiologically active substance may be used in the form of a salt with an inorganic acid (for example, hydrochloric acid, sulfuric acid, nitric acid or the like) or an organic acid (for example, carbonic acid, succinic acid, or the like).
  • the physiologically active substance has an acidic group such as carboxy
  • it may be used in the form of a salt with an inorganic base (for example, an alkali metal such as sodium, potassium or the like) or an organic base (for example, an organic amine such as triethylamine or the like, a basic amino acid such as arginine or the like).
  • an inorganic base for example, an alkali metal such as sodium, potassium or the like
  • an organic base for example, an organic amine such as triethylamine or the like, a basic amino acid such as arginine or the like.
  • a biodegradable polymer used in the present invention is a lactic acid-glycolic acid copolymer in which the weight-average molecular weight (Mw) is about 8,000 to about 11,500, the ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) is larger than 1.9, and the compositional molar ratio of lactic acid to glycolic acid is 99.9/0.1 to 60/40, or a salt thereof.
  • a salt of the lactic acid-glycolic acid copolymer includes, for example, a salt with an inorganic base (for example, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, or the like), a salt with an organic base (for example, an organic amine such as triethylamine, a basic amino acid such as arginine, or the like), a salt with a transition metal (for example, zinc, iron, cupper or the like), a complex salt and the like.
  • an inorganic base for example, an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or magnesium, or the like
  • an organic base for example, an organic amine such as triethylamine, a basic amino acid such as arginine, or the like
  • a salt with a transition metal for example, zinc, iron, cupper or the like
  • the ratio (Mw/Mn) of the weight-average molecular weight (Mw) of the lactic acid-glycolic acid copolymer to the number-average molecular weight (Mn) of the lactic acid-glycolic acid copolymer is 2.3 to 3.1.
  • compositional ratio (mol%) of the lactic acid-glycolic acid copolymer is preferably 99/1 to 60/40, more preferably 90/10 to 60/40, and still more preferably 80/20 to 60/40, particularly preferably 80/20 to 70/30, and most preferably 75/25.
  • the weight average molecular weight of the above-described lactic acid-glycolic acid copolymer is usually about 8,000 to about 11,500, preferably about 9,000 to about 11,500, and more preferably about 9,500 to 11,000.
  • a weight-average molecular weight and a number-average molecular weight refer to the molecular weights (weight-average molecular weight and number-average molecular weight) that is measured by gel permeation chromatography (GPC) using several kinds of polystyrenes having certain weight-average molecular weights as standard substances, followed by calibration with polystyrene.
  • Dispersivity as used herein refers to the dispersivity calculated from the molecular weights obtained as described above.
  • a column and a mobile phase used in the measurement can be appropriately selected.
  • a lactic acid-glycolic acid copolymer is dissolved in dichloromethane, added water, and partitioned.
  • the dichloromethane layer is titrated with an ethanolic potassium hydroxide solution using an automatic titrating apparatus and the amount of terminal carboxylic acid is calculated, whereby the number-average molecular weight can be calculated.
  • this is expressed as a number-average molecular weight by means of terminal group quantitation.
  • a number-average molecular weight by means of terminal group quantitation is absolute value, while a number-average molecular weight by means of GPC measurement is relative value varying depending on assay and analysis conditions (for example, the kind of a mobile phase, the kind of a column, a standard substance, selection of the width of slice, selection of a baseline and the like).
  • the number-average molecular weight by means of GPC measurement and the number-average molecular weight by means of terminal group quantitation are approximately the same value.
  • the number-average molecular weight of this lactic acid-glycolic acid copolymer “approximately the same” means that the number-average molecular weight by means of terminal group quantitation is in the range from about 0.2 to about 1.5 times, preferably from about 0.3 to about 1.2 times the number-average molecular weight by means of GPC measurement.
  • the GPC method (1) described in Reference Example 1 is a GPC method comprising using 8 polystyrene standard products whose weight-average molecular weights (Mw) evaluated by a GPC method are 98,900, 37,200, 17,100, 9, 490, 5,870, 2, 500, 1,051, and 495 respectively.
  • the GPC method (2) described in Reference Example 1 is a GPC method comprising using a total of 8 polystyrene standard products consisting of 6 polystyrene standard products whose weight-average molecular weights (Mw) evaluated by a light scattering method are 96,400, 37,900, 18,100, 10,200, 5, 970 and 2,630 respectively and 2 polystyrene standard products whose weight-average molecular weights (Mw) measured by a GPC method whose are 1,051 and 495 respectively.
  • the weight-average molecular weight and the number-average molecular weight of the above-described lactic acid-glycolic acid copolymer or a salt thereof used in the present invention can be measured by, for example, the GPC method (1) described in Reference Example 1.
  • lactic acid-glycolic acid copolymers and the like are preferably used.
  • the degradation and/or elimination rate of a lactic acid-glycolic acid copolymer varies greatly depending on the composition or molecular weight of the polymer. Generally, the lower the percentage of glycolic acid in the polymer is, the more the degradation/elimination is delayed. Therefore, a releasing period of a drug can be extended by lowering the percentage of glycolic acid in the polymer or by increasing the molecular weight of the polymer. Conversely, a releasing period can be shortened by increasing the percentage of glycolic acid or by decreasing the molecular weight.
  • a lactic acid-glycolic acid copolymer having a compositional ratio and a weight-average molecular weight in the above-mentioned range it is preferable to use a lactic acid-glycolic acid copolymer having a compositional ratio and a weight-average molecular weight in the above-mentioned range.
  • a lactic acid-glycolic acid copolymer which is degraded more rapidly than a lactic acid-glycolic acid copolymer having a compositional ratio and a weight-average molecular weight in the above-mentioned range is selected, it is difficult to suppress the initial burst of the resulting sustained-release preparation.
  • the resulting preparation tends to have a period during which an effective amount of a drug is not released after administration.
  • a lactic acid-glycolic acid copolymer can be produced by, for example, non-catalytic dehydration polycondensation from lactic acid and glycolic acid ( JP-A 61-28521 ) or ring opening polymerization using a catalyst from cyclic forms such as lactide and glycolide ( Encyclopedic Handbook of Biomaterials and Bioengineering Part A: Materials, Volume 2, Marcel Dekker, Inc. 1995 ).
  • a polymer synthesized by ring opening polymerization is a polymer having no carboxyl group
  • such a polymer may be subjected to chemical treatment to change the terminal into free carboxyl, which may be also used ( J. Controlled Release, Vol.41, pp.249-257, 1996 ).
  • the above-described lactic acid-glycolic acid copolymer having free carboxyl at the terminal can be easily produced by a known method (for example, non-catalytic dehydration polycondensation method, see JP-A 61-28521 ). Further, a polymer having free carboxyl at any position that is not limited to the terminal can be produced by a known method (for example, see WO94/15587 ).
  • the lactic acid-glycolic acid copolymer whose terminal is changed into free carboxyl by chemical treatment after ring opening polymerization may be commercially available, for example, from Boehringer Ingelheim KG.
  • the lactic acid-glycolic acid copolymer produced by ring opening polymerization is hydrolyzed in the presence of an acid or a base in accordance with a known method.
  • the hydrolysis is performed in the presence of water.
  • the acid includes inorganic acids such as hydrochloric acid, nitric acid, sulfuric acid and phosphoric acid, and organic acids such as lactic acid, acetic acid, tartaric acid, citric acid and succinic acid.
  • the base includes alkali metal hydroxide such as sodium hydroxide and potassium hydroxide, and alkali metal carbonate such as sodium carbonate and potassium carbonate. In the case where the hydrolysis is performed in the presence of a base, release of a physiologically active substance from the sustained-release microcapsule is affected by the remaining amount of the base. Therefore, it is preferable that the hydrolysis is performed in the presence of an acid.
  • the hydrolysis is usually performed in a solvent which have no adverse effect on the reaction.
  • a solvent includes alcohols such as methanol, ethanol and propanol, ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether, water, and a mixed solvent thereof.
  • alcohols such as methanol, ethanol and propanol
  • ethers such as tetrahydrofuran, dioxane, diethyl ether and diisopropyl ether
  • water and a mixed solvent thereof.
  • an excessive amount of the above-described acid or base may be used as a solvent.
  • a temperature upon the hydrolysis is, for example, about 0 to about 100°C, preferably about 10 to about 100°C.
  • the time necessary for the hydrolysis varies depending on the weight-average molecular weight of a lactic acid-glycolic acid copolymer produced by ring opening polymerization, the kind of an acid or a base, the kind of a solvent, temperature and the like, it may be appropriately determined by collecting a portion of a lactic acid-glycolic acid copolymer during hydrolysis and then measuring the weight-average molecular weight of the collected lactic acid-glycolic acid copolymer.
  • the time necessary for the hydrolysis is not particularly limited, but it is, for example, about 1 hour to about 10 days, preferably about 10 hours to about 5 days.
  • a sustained-release microcapsule that induces a great initial burst can be produced from a lactic acid-glycolic acid copolymer produced by ring opening polymerization.
  • a sustained-release microcapsule that induces a small initial burst can be produced from a hydrolyzed lactic acid-glycolic acid copolymer, that is to say, the lactic acid-glycolic acid copolymer used in the present invention.
  • the hydrolyzed lactic acid-glycolic acid copolymer is further subjected to a purification step.
  • the purification step is performed by dissolving the hydrolyzed lactic acid-glycolic acid copolymer in an organic solvent, pouring the obtained solution into water or a mixed solution of water and a water-soluble organic solvent and then separating a precipitated lactic acid-glycolic acid copolymer.
  • the organic solvent includes, for example, halogenated hydrocarbons (for example, dichloromethane, chloroform, chloroethane, dichloroethane, trichloroethane, carbon tetrachloride and the like), ketones (for example, acetone and the like), ethers (for example, tetrahydrofuran, ethyl ether, isopropyl ether and the like), esters (for example, ethyl acetate, butyl acetate and the like), aromatic hydrocarbons (for example, benzene, toluene, xylene and the like) and the like.
  • the amount of the organic solvent used is, for example, about 3 to about 20 times (w/v) the amount of the hydrolyzed lactic acid-glycolic acid copolymer used.
  • the water-soluble organic solvent includes, for example, acetone, methanol, ethanol, tetrahydrofuran, acetonitrile and the like.
  • the amount of water or a mixed solution of water and the water-soluble organic solvent to be used is not particularly limited, but it is usually a greatly excessive amount relative to the amount of hydrolyzed lactic acid-glycolic acid copolymer used.
  • the temperature in the purification step is usually about 0 to about 90°C, preferably about 20 to about 70°C.
  • Water-soluble low-molecular compounds for example, compounds having a weight-average molecular weight of about 1,000 or less
  • the lactic acid-glycolic acid copolymer obtained via such purification step is used to produce a sustained-release microcapsule
  • the incorporation rate (trapping rate) of a physiologically active substance into the resulting sustained-release microcapsule can be enhanced, and moreover, the resulting sustained release preparation can induce a reduced initial burst.
  • a lactic acid-glycolic acid copolymer that does not substantially contain a harmful catalyst used in ring opening polymerization for example, a zinc compound such as zinc oxide or a tin compound such as stannous octanoate
  • a harmful catalyst used in ring opening polymerization for example, a zinc compound such as zinc oxide or a tin compound such as stannous octanoate
  • a harmful catalyst used in ring opening polymerization for example, a zinc compound such as zinc oxide or a tin compound such as stannous octanoate
  • a drug retaining substance is a substance characterized in that it is water-soluble, hardly soluble in an organic solvent if a oil phase, becomes a semi-solid that is already highly viscous in the state of being dissolved in water, or the viscosity is remarkably increased by some extrinsic factors such as temperature, pH, a metal ion (for example, Cu 2+ , Al 3+ , Zn 2+ and the like), organic acid (for example, tartaric acid, citric acid, tannic acid and the like) or its salt, a chemical condensing agent (for example, glutaraldehyde, acetoaldehyde and the like) to become a semi-solid or solid matrix.
  • a metal ion for example, Cu 2+ , Al 3+ , Zn 2+ and the like
  • organic acid for example, tartaric acid, citric acid, tannic acid and the like
  • a chemical condensing agent for example, glutaraldehyde,
  • Examples of a drug retaining substance are natural and synthetic gums and high-molecular compounds.
  • Natural gums include acacia gum, gum arabic, Irish moss, karaya gum, tragacanth gum, guaiac gum, xanthan gum, and locust bean gum.
  • Natural high-molecular compounds include protein such as casein, gelatin, collagen, albumin (for example, human serum albumin), globulin, and fibrin, and carbohydrate such as cellulose, dextrin, pectin, starch, agar, and mannan.
  • These may be as they are, or may be partially chemically modified synthetic gums, for example, the above-mentioned natural gums which have been esterified or etherized (for example, methylcellulose, ethylcellulose, carboxylmethylcellulose, gelatin succinate and the like), or hydrolyzed (for example, sodium alginate, sodium pectinate and the like), or their salts.
  • synthetic gums for example, the above-mentioned natural gums which have been esterified or etherized (for example, methylcellulose, ethylcellulose, carboxylmethylcellulose, gelatin succinate and the like), or hydrolyzed (for example, sodium alginate, sodium pectinate and the like), or their salts.
  • Synthetic high-molecular compounds include, for example, polyvinyl compounds (for example, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl ether and the like), polycarboxylic acid (for example, polyacrylic acid, polymethacrylic acid, Carbopol (Goodrich, Co., Ltd.) and the like), polyethylene compounds (for example, polyethylene glycol and the like), polysaccharide (for example, polysucrose, polyglucose, polylactose and the like), and their salts.
  • polyvinyl compounds for example, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl methyl ether, polyvinyl ether and the like
  • polycarboxylic acid for example, polyacrylic acid, polymethacrylic acid, Carbopol (Goodrich, Co., Ltd.) and the like
  • polyethylene compounds for example, polyethylene glycol and the like
  • polysaccharide for
  • gelatin is suitable for a drug retaining substance.
  • the sustained-release composition of the present invention may be in any form including a sustained-release microsphere (a sustained-release microcapsule is included) and a sustained-release microparticle, and it is preferably in the form of a sustained-release microcapsule.
  • a sustained-release microsphere refers to an injectable spherical microparticle capable of being dispersed in a solution. Confirmation of the form can be performed, for example, by observation with a scanning electron microscope.
  • the sustained-release microcapsule may contain fine particles (that is, microspheres) containing a physiologically active substance and a lactic acid-glycolic acid copolymer or a salt thereof.
  • the fine particle include a microcapsule containing one core of a physiologically active substance in one particle, a polynuclear microcapsule containing a plurality of cores of a physiologically active substance in one particle, and a microparticle in which a molecular physiologically active substance as a solid solution is dissolved or dispersed in a raw lactic acid-glycolic acid copolymer or a salt thereof.
  • the content of a physiologically active substance in the sustained-release composition of the present invention varies depending on the kind of the physiologically active substance, the desired pharmacological effect, duration of the effect and the like, and for example, it is about 0.01 to about 50%(w/w), preferably about 0.1 to about 30%(w/w), more preferably about 5 to about 24% (w/w).
  • sustained-release microcapsule which is a representative example of the sustained-release composition of the present invention will be described in detail.
  • the sustained-release microcapsule of the present invention is produced by mixing (i) a solution containing a physiologically active substance and not containing a drug retaining substance and (ii) a solution adjusted to about 25 to about 35°C and containing a lactic acid-glycolic acid copolymer or a salt thereof (hereinafter, abbreviated as the biodegradable polymer) in which the weight-average molecular weight (Mw) is about 8,000 to about 11,500, the ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) is 2.3 to 3.1, and the compositional molar ratio of lactic acid to glycolic acid is 99.9/0.1 to 60/40, to prepare a W/O emulsion of about 25 to about 35°C (primary emulsification); cooling the W/O emulsion to about 15 to about 20°C; dispersing the W/O emulsion into an aqueous phase to prepare a W/O/
  • the W/O emulsion that comprises a solution containing a physiologically active substance and not containing a drug retaining substance as an inner aqueous phase, and a solution adjusted to about 25 to about 35°C and containing the biodegradable polymer as an oil phase can be produced as follows.
  • a physiologically active substance is dissolved in water (preferably, distilled water for injection) at a concentration of about 0.001 to about 90% (w/w), preferably about 0.01 to about 80% (w/w), more preferably about 1 to about 70% (w/w), particularly preferably about 50%, to form an inner aqueous phase.
  • a pH adjusting agent such as carbonic acid, acetic acid, oxalic acid, citric acid, phosphoric acid, hydrochloric acid, sodium hydroxide, arginine, lysine, or a salt thereof, for the purpose of maintaining the stability and solubility of the physiologically active substance.
  • a stabilizing agent for the physiologically active substance such as albumin, gelatin, trehalose, citric acid, sodium ethylenediamine tetraacetate, dextrin, cyclodextrin ( ⁇ -, ⁇ -, ⁇ -) and a derivative thereof (for example, maltosyl ⁇ -cyclodextrin, ⁇ -cyclodextrin sulfobutyl ether or the like), sodium hydrogen sulfite, a polyol compound such as polyethylene glycol, a surfactant such as polyoxyethylene sorbitan fatty acid ester [for example, Tween 80, Tween 60 (Kao Corporation, Japan)] or a polyoxyethylene caster oil derivative [for example, HCO-60, HCO-70 (Nikko Chemicals Co., Ltd., Japan)], parahydroxybenzoic acid ester (for example, methylparaben, propylparaben or the like), benzyl alcohol, chloro
  • the inner aqueous phase thus obtained is mixed with a solution adjusted to about 25 to about 35°C and containing the biodegradable polymer (oil phase).
  • the mixture is subjected to an emulsification step to prepare a W/O emulsion.
  • the solution containing the biodegradable polymer (oil phase) to be used is a solution of the biodegradable polymer in an organic solvent.
  • the organic solvent may be a solvent which has a boiling point of about 120°C or lower, is hydrophobic and can dissolve the biodegradable polymer, and includes, for example, halogenated hydrocarbons (for example, dichloromethane (methylene chloride), chloroform, chloroethane, dichloroethane, trichloroethane, carbon tetrachloride and the like), fatty acid esters (for example, ethyl acetate, butyl acetate and the like), ethers (for example, ethyl ether, isopropyl ether and the like), aromatic hydrocarbons (for example, benzene, toluene, xylene and the like), and the like. Two or more kinds of these organic solvents may be mixed at an appropriate ratio and used.
  • the organic solvent is preferably
  • the concentration of the biodegradable polymer in the organic solvent varies depending on the kind and molecular weight of the biodegradable polymer, and the kind of the organic solvent, and it is usually about 0.01 to about 90% (w/w), preferably about 0.1 to about 80% (w/w), more preferably about 1 to 70% (w/w), particularly preferably about 35%.
  • a hydrophilic organic solvent such as ethanol, acetonitrile, acetone or tetrahydrofuran may be partially added to the oil phase.
  • a surfactant such as sucrose fatty acid ester may be added.
  • the oil phase thus obtained is usually used after removing bacteria and dusts by filtration using a filter.
  • the solution containing the biodegradable polymer may be stored in a sealed container at room temperature or in cold places, depending on the stability of the biodegradable polymer.
  • the mixing ratio between the solution containing a physiologically active substance and not containing a drug retaining substance and the biodegradable polymer solution is about 0.1 to about 1000 parts by weight, preferably about 1 to about 100 parts by weight, more preferably about 1 to about 20 parts by weight, particularly preferably about 10 parts by weight of the latter per 1 part by weight of the former.
  • the mixing ratio of a physiologically active substance to the biodegradable polymer is about 0.01 to about 50% (w/w), preferably about 0.5 to about 40% (w/w), more preferably about 0.1 to about 30% (w/w), particularly preferably about 10%, depending on the kind of the physiologically active substance, the desired pharmacological effect, duration period of the effect and the like.
  • the emulsification step is carried out by a known dispersing method, for example, an intermittent vibration method, a method using a stirrer such as propeller-type stirrer or a turbine-type stirrer, a colloid mill method, a homogenizer method, an ultrasound irradiation method or the like.
  • a known dispersing method for example, an intermittent vibration method, a method using a stirrer such as propeller-type stirrer or a turbine-type stirrer, a colloid mill method, a homogenizer method, an ultrasound irradiation method or the like.
  • the solution containing a physiologically active substance and not containing a drug retaining substance and the solution containing the biodegradable polymer are mixed at about 25 to about 35°C, preferably about 27 to about 33°C.
  • a sustained-release microcapsule having improved spherical property and/or improved needle penetrating property can be produced.
  • the solution containing the biodegradable polymer is added to a container containing the solution containing a physiologically active substance and not containing a drug retaining substance. Then, the container is vibrated or swung, thereby rough emulsification is performed. In rough emulsification, it is preferable that the temperature of a mixture of the solution containing a physiologically active substance and not containing a drug retaining substance and the solution containing the biodegradable polymer is adjusted to about 25 to about 35°C, preferably about 27 to about 33°C.
  • a purpose of rough emulsification is to facilitate the next emulsification step (precise emulsification), and the stirring time, and the vibration and swinging number are not particularly defined. Therefore, if precise emulsification can be carried out uniformly, the rough emulsification step may be omitted.
  • the mixture after the rough emulsification is subjected to an emulsification step (precise emulsification) using a propeller-type stirrer or the like.
  • emulsification step precision emulsification
  • the temperature of a mixture of the solution containing a physiologically active substance and not containing a drug retaining substance and the solution containing the biodegradable polymer is adjusted to about 25 to about 35°C, preferably about 27 to about 33°C.
  • the emulsification time of the precise emulsification step can be selected depending on the properties of the physiologically active substance and the biodegradable polymer, and generally, it is about 0.1 to about 60 minutes.
  • the volume of the oil phase to be mixed is about 1 to about 1000 times, preferably about 2 to about 100 times, more preferably about 3 to 10 times the volume of the inner aqueous phase.
  • the viscosity of the resulting W/O emulsion is generally in the range of about 10 to about 10,000 cp, preferably about 100 to 5,000 cp, particularly preferably about 500 to about 2,000 cp at about 12 to 25°C.
  • the W/O emulsion obtained by precise emulsification is cooled in a water bath or the like at 0 to 18°C to adjust the temperature of the W/O emulsion to about 0 to about 30°C, preferably about 10 to about 25°C, more preferably about 15 to 20°C.
  • the W/O emulsion thus obtained is dispersed in an aqueous phase (hereinafter, abbreviated as outer aqueous phase) to prepare a W/O/W emulsion.
  • the W/O/W emulsion is subjected to in-water drying to produce a sustained-release microcapsule.
  • the emulsifier may be added to the above-described outer aqueous phase.
  • the emulsifier may be any emulsifier that usually forms a stable W/O emulsion, and includes, for example, anion surfactants (for example, sodium oleate, sodium stearate, sodium lauryl sulfate and the like), nonionic surfactants (for example, Tween 80, Tween 60, HCO-60, HCO-70 and the like), polyvinyl alcohol, polyvinylpyrrolidone, gelatin and the like. Two or more kinds of these emulsifiers may be mixed at an appropriate ratio and used. In the process of the present invention, polyvinyl alcohol is preferably used as an emulsifier.
  • the concentration of an emulsifier in the outer aqueous phase is, for example, about 0.001 to about 20%, preferably about 0.01 to about 10%, more preferably about 0.05 to about 5%, particularly preferably about 0.1%.
  • An osmotic pressure regulating agent may be added to the above-described outer aqueous phase.
  • the osmotic pressure regulating agent may be any agent that exhibits an osmotic pressure when it is put into an aqueous solution.
  • the osmotic pressure regulating agent includes, for example, polyhydric alcohols, monohydric alcohols, monosaccharides, disaccharides, oligosaccharides and amino acids and their derivatives, and sodium chloride.
  • the polyhydric alcohols include, for example, trihydric alcohols such as glycerin, pentahydric alcohols such as arabitol, xylitol and adonitol, and hexahydric alcohols such as mannitol, sorbitol and dulcitol.
  • trihydric alcohols such as glycerin
  • pentahydric alcohols such as arabitol, xylitol and adonitol
  • hexahydric alcohols such as mannitol, sorbitol and dulcitol.
  • hexahydric alcohols are preferably used, and in particular, mannitol is suitably used.
  • the monohydric alcohols include, for example, methanol, ethanol and isopropyl alcohol, and among them, ethanol is preferably used.
  • the monosaccharides include, for example, pentose such as arabinose, xylose, ribose and 2-deoxyribose, and hexose such as glucose, fructose, galactose, mannose, sorbose, rhamnose and fucose, and among them, hexose is preferably used.
  • the oligosaccharides include, for example, trisaccharides such as maltotriose and raffinose saccharides, and tetrasaccharides such as stachyose, and among them, trisaccharides are preferably used.
  • the derivatives of monosaccharides, disaccharides and oligosaccharides include, for example, glucosamine, galactosamine, glucuronic acid, and galacturonic acid.
  • amino acid any amino acid can be used as long as it is L-isomer and the examples include glycine, leucine and arginine. Among them, L-arginine is preferably used.
  • osmotic pressure regulating agents may be used alone or may be used by mixing them.
  • An osmotic pressure regulating agent is used at such a concentration that the osmotic pressure of the outer aqueous phase is about 1/50 to about 5 times, preferably about 1/25 to about 3 times, more preferably about 1/12 to about 2 times the osmotic pressure of a physiological saline.
  • the concentration of the osmotic pressure regulating agent in the outer aqueous phase is about 0.01% to about 60% (w/w), preferably about 0.01 to about 40% (w/w), more preferably about 0.05 to about 30% (w/w), particularly preferably about 0.5 to about 1.5% (w/w).
  • an osmotic pressure regulating agent is an ionic substance
  • a concentration obtained by dividing the above-described concentration by the whole ionic valency is used.
  • the concentration of an osmotic regulating agent to be added is not necessary to be the solubility or lower, and a part of the agent may be in the dispersed state.
  • the dispersivity of the produced microcapsule can be improved by adding an osmotic pressure regulating agent to the outer aqueous phase.
  • the extent of dispersivity is particularly not limited, but, for example, it is preferable that about 400 to 700 mg of the microcapsule can be dispersed in 1.5 mL of a dispersing medium for injection in less than two minutes.
  • Removal of an organic solvent may be performed in accordance with a known method.
  • a method includes, for example, a method of removing the solvent under the normal pressure or gradually reduced pressure while stirred with a propeller-type stirrer, a magnetic stirrer or the like, and a method of removing the solvent using a rotary evaporator or the like while the vacuum degree and the temperature are regulated.
  • the sustained-release microcapsule thus obtained is collected by centrifugation, filtration, wet cyclone or the like, washed with distilled water repeatedly.several times to remove a free physiologically active substance, an emulsifier and the like which are adhered to the surface of the microcapsule. Subsequently, the washed microcapsule is dried under reduced pressure, or is redispersed in distilled water and then lyophilized to further remove an organic solvent.
  • an aggregation preventing agent may be added.
  • the aggregation preventing agent includes, for example, water soluble polysaccharides such as mannitol, lactose, glucose and starches (for example, corn starch and the like), amino acids such as glycine, and proteins such as fibrin and collagen. Among them, mannitol is preferably used.
  • the amount of an aggregation preventing agent such as mannitol to be added is usually 0 to about 24% by weight of the total amount of the microcapsules.
  • the sustained-release microcapsule of the present invention preferably contains an excipient. It is desired that the excipient is low in toxicity even when administered to a living body, is easily dried such as by lyophilization, and is rapidly dissolved when administered to a living body or is dissolved upon use.
  • an excipient includes, for example, sugars, cellulose derivatives, amino acids, proteins, polyacrylic acid derivatives, organic salts, and inorganic salts. Two or more kinds of these excipients may be mixed and used at an appropriate ratio.
  • the sugars include, for example, D-mannitol, sodium alginate, fructose, dextran, dextrin, white sugar, D-sorbitol, lactose, glucose, maltose, starches and trehalose.
  • the cellulose derivatives include, for example, carboxymethylcellulose, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, and hydroxymethylcellulose acetate succinate.
  • the amino acids include, for example, glycine, alanine, tyrosine, arginine, and lysine.
  • the proteins include, for example, fibrin, collagen, and albumin.
  • the polyacrylic acid derivatives include, for example, sodium polyacrylate, and methacrylic acid/acrylic acid copolymers (Eudragit, Rohm, Co., Ltd., Germany).
  • the organic salts include, for example, sodium citrate, sodium tartrate, sodium carbonate, and potassium carbonate.
  • the inorganic salts include, for example, sodium chloride, potassium chloride, sodium phosphate, and potassium phosphate.
  • water-soluble polymers in which the polymer that is the base of the sustained-release microcapsule is not dissolved, for example, polyvinylpyrrolidone and polyvinyl alcohol are also used.
  • the excipient is preferably a sugar, and inter alia, D-mannitol which is easily lyophilized and has little toxicity.
  • an excipient used is determined depending on the solubility of the excipient, the tonicity, viscosity, dispersivity and stability of a solution of the excipient and the like.
  • an excipient is used so that the content of the excipient in the dried sustained-release microcapsule is, for example, about 0.5 to about 99% (w/w), preferably about 1 to 90% (w/w), more preferably about 2 to about 60% (w/w).
  • the content of the excipient in the dried sustained-release microcapsule is about 2 to about 40% (w/w), preferably about 15% (w/w).
  • the following excellent effects are obtained: 1) the frequency of contact and collision of particles during and after drying the sustained-release microcapsule is reduced, and thereby uniformity of the particles at lyophilization is maintained, 2) the sustained-release microcapsule can be dried at the glass transition temperature or higher, and thereby water or an organic solvent can be removed more completely, and 3) the stability with time of the sustained-release microcapsule is improved, and thereby a sustained-release microcapsule which has better dispersivity, can be stored in any place including but not limited to cold places, and has a long term limit for use, for example, at room temperature is obtained.
  • the sustained-release microcapsule containing an excipient can be produced, for example, by mixing a microcapsule obtained by the above-described in-water drying method with an excipient.
  • the microcapsule obtained by the above-described in-water drying method may be used after washed and then dried under reduced pressure, or after washed, redispersed in distilled water and then lyophilized.
  • a method of mixing is not particularly limited, and for example, mixing is carried out by using a mixer.
  • the sustained-release microcapsule containing an excipient can be also produced by using an aqueous solution of an excipient as the outer aqueous phase when the W/O/W emulsion to be subjected to in-water drying is produced.
  • the sustained-release microcapsule containing an excipient is preferably produced by washing a microcapsule obtained by the in-water drying method, dispersing the washed microcapsule in distilled water in which an excipient has been dissolved or suspended, and then subjecting the dispersion to lyophilization or drying under reduced pressure.
  • the washed microcapsule may be dispersed in distilled water, and an excipient may be dissolved or suspended in the obtained dispersion, followed by lyophilization or drying under reduced pressure.
  • an uniform mixture is obtained by dispersing the washed microcapsule in distilled water in which an excipient had been dissolved, or by dispersing the washed microcapsule in distilled water, dissolving an excipient in the obtained dispersion and then lyophilizing the dispersion.
  • water and an organic solvent in the microcapsule can be removed more completely and, at the same time, sustained-release can be improved by heating the microcapsule obtained by the above-described in-water drying method to a temperature which is the glass transition temperature (Tg) or higher of the polymer used as a base and at which particles of the microcapsules are not attached to each other.
  • Tg glass transition temperature
  • an organic solvent is removed to less than about 1,000 ppm, preferably less than about 500 ppm, more preferably less than about 100 ppm of the organic solvent concentration in the microcapsule.
  • a glass transition temperature refers to an intermediate point glass transition temperature obtained when the temperature is raised at a heating rate of 10 or 20°C per minute using a differential scanning calorimeter (DSC).
  • DSC differential scanning calorimeter
  • the timing of heating is preferably after optional addition of an excipient and after lyophilization or drying under reduced pressure, but it is not particularly limited and for example, it may be after dispensing.
  • the heating temperature When the heating temperature is lower than the glass transition temperature of the polymer used as a base, removal of water or an organic solvent is insufficient in some cases. On the other hand, when the heating temperature is too high, the risk of fusion and deformation of the microcapsules, and degradation and deterioration of the physiologically active substance is increased. Thus, the heating temperature can not be unconditionally defined, but can be appropriately determined in view of physical properties (for example, molecular weight, stability and the like) of the polymer used as a base, the average particle diameters of the physiologically active substance and microcapsule, the heating time, the drying degree of the microcapsule, a method of heating and the like.
  • physical properties for example, molecular weight, stability and the like
  • the heating temperature is preferably in the range from the glass transition temperature of the polymer used as a base to about 40°C higher temperature than the glass transition temperature, more preferably from the glass transition temperature of the polymer to 35°C higher temperature than the glass transition temperature, still more preferably from the glass transition temperature of the polymer to 25°C higher temperature than the glass transition temperature, particularly preferably from the glass transition temperature of the polymer to 20°C higher temperature than the glass transition temperature.
  • the heating time varies depending on the heating temperature, the amount of microcapsules to be treated and the like, and is generally about 6 to 120 hours, more preferably about 12 to 96 hours after the temperature of the microcapsule is reached to the predetermined temperature.
  • the upper limit of the heating time is not particularly limited as long as the amounts of a remaining organic solvent and water become an acceptable amount or lower.
  • the microcapsule is softened, and deformed due to physical contact between the microcapsules or loading at lamination of the microcapsules. Therefore, it is preferable that the heating is rapidly terminated when the amounts of a remaining organic solvent and water become an acceptable amount or lower.
  • a method of heating is not particularly limited, and any method may be used as long as it can heat microcapsules uniformly.
  • a preferable example of such a heating method includes a method comprising heating and drying under reduced pressure using a lyophilizing machine, a reduced pressure constant temperature machine or the like.
  • the sustained-release composition including a sustained-release microcapsule of the present invention may be in the form of an injection, an implant, a oral preparation (for example, powder, granule, capsule, tablet, syrup, emulsion, suspension or the like), a transnasal preparation, a suppository (for example, rectal suppository, vaginal suppository or the like) or the like, and can be produced by a method usually known in the pharmaceutical field.
  • a oral preparation for example, powder, granule, capsule, tablet, syrup, emulsion, suspension or the like
  • a transnasal preparation for example, a suppository (for example, rectal suppository, vaginal suppository or the like) or the like, and can be produced by a method usually known in the pharmaceutical field.
  • a suppository for example, rectal suppository, vaginal suppository or the like
  • an injection is produced by dispersing the above-described microcapsules into an aqueous or oily dispersion medium.
  • An aqueous dispersion medium includes, for example, a solution in which an isotonic agent (for example, sodium chloride, glucose, D-mannitol, sorbitol, glycerin or the like), a dispersing agent (for example, Tween 80, HCO-50, HCO-60, carboxymethylcellulose, sodium alginate or the like), a preservative (for example, benzyl alcohol, benzalconium chloride, phenol or the like), a shoothing agent (for example, glucose, calcium gluconate, procaine hydrochloride or the like) or the like is dissolved.
  • An oily dispersion medium includes, for example, olive oil, sesame oil, peanut oil, soybean oil, corn oil, and medium chain fatty acid glyceride.
  • the chamber of a prefilled syringe may be filled with the injection.
  • the two different chambers of a so-called double chamber prefilled syringe (DPS) may be filled with a dispersion medium and the microcapsules separately.
  • a more stable sustained-release injection is obtained by, in producing the injection, adding an excipient (for example, mannitol, sorbitol, lactose, glucose or the like) in addition to the above-described ingredients to the microcapsules, dispersing again it, lyophilizing or spraying-drying the dispersion to solidify it, and then adding distilled water for injection or a suitable dispersion medium to the solid before use.
  • an excipient for example, mannitol, sorbitol, lactose, glucose or the like
  • An oral preparation can be produced, for example, by adding an excipient (for example, lactose, white sugar, starch or the like), a disintegrant (for example, starch, calcium carbonate or the like), a binder (for example, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxypropylcellulose or the like), a lubricant (for example, talc, magnesium stereate, polyethylene glycol 6000 or the like) and the like to the above-described microcapsules, compressing and molding the mixture, and then, if necessary, coating it by means of a per se known method for the purpose of masking of taste, enteric coating or sustained-release.
  • an excipient for example, lactose, white sugar, starch or the like
  • a disintegrant for example, starch, calcium carbonate or the like
  • a binder for example, starch, gum arabic, carboxymethylcellulose, polyvinylpyrrolidone, hydroxyprop
  • a coating agent includes, for example, hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyehtylene glycol, Tween 80, Pluronic F 68 , cellulose acetate phthalate, hydroxypropylmethycellulose phthalate, hydroxymethylcellulose acetate succinate, Eudragit (made by Rohm, Co., Ltd., Germany, methacrylic acid/acrylic acid copolymer) and pigments (for example, titanium dioxide, colcothar and the like).
  • a transnasal preparation may be in the form of a solid, a semi-solid, or liquid.
  • a transnasal preparation in the form of a solid may be, for example, the above-described microcapsule as it is, but usually it can be produced by adding an excipient (for example, glucose, mannitol, starch, microcrystalline cellulose or the like), a thickening agent (for example, natural gums, cellulose derivatives, acrylic acid polymers or the like) and the like to the microcapsules and mixing them.
  • an excipient for example, glucose, mannitol, starch, microcrystalline cellulose or the like
  • a thickening agent for example, natural gums, cellulose derivatives, acrylic acid polymers or the like
  • a transnasal preparation in the form of liquid can be produced in a similar manner to the case of the above-described injection.
  • the transnasal preparation may contain a pH adjusting agent (for example, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide or the like), an antiseptic agent (for example, parahydroxybenzoic acid esters, chlorobutanol, benzalconium chloride or the like) and the like.
  • a pH adjusting agent for example, carbonic acid, phosphoric acid, citric acid, hydrochloric acid, sodium hydroxide or the like
  • an antiseptic agent for example, parahydroxybenzoic acid esters, chlorobutanol, benzalconium chloride or the like
  • a suppository may be oily or aqueous, and may be in the form of a solid, a semi-sold or liquid.
  • a suppository is usually produced using an oily base, an aqueous base or an aqueous gel base.
  • An oily base includes, for example, higher fatty acid glyceride [for example, cacao butter, Witepsol-series products (Dynamite Nobel), etc.], medium fatty acid [e.g., Miglyol-series products (Dynamite Nobel), etc.], vegetable oil (e.g., sesame oil, soybean oil, cottonseed oil, etc.) and the like.
  • An aqueous base includes, for example, polyethylene glycol, propylene glycol and the like.
  • An aqueous gel base includes, for example, natural gums, cellulose derivatives, vinyl polymers, acrylic acid polymers, and the like.
  • sustained-release composition of the present invention include sustained-release microcapsules described in Example A1-A3.
  • the sustained-release composition, particularly the sustained-release microcapsule, of the present invention is preferably an injection.
  • the particle diameter of the sustained-release composition as an injection may be in such a range that its dispersivity and needle penetrating property are satisfied, and it is, for example, an average diameter of about 0.1 to about 1,000 ⁇ m, preferably about 1 to about 300 ⁇ m, more preferably about 5 to about 150 ⁇ m.
  • the desolvation rate is high.
  • the concentration of remaining methylene chloride in the composition after in-water drying is usually about 2,000 ppm to about 20,000 ppm. Therefore, the sustained-release composition of the present invention is excellent in desolvation property.
  • the sustained-release composition of the present invention has an excellent characteristic of a slow sedimentation rate.
  • the sedimentation rate can be determined, for example, by putting 50 mg of the sustained-release microcapsule powder of the present invention in a vial, suspending the powder in 5 mL of a dispersion medium, dispersing about 40 ⁇ L of the obtained suspension in 5 mL of a dispersion medium, and measuring NTU with a turbidimeter.
  • the sustained-release composition of the present invention has a characteristic that it takes a long time for the turbidity to reach 50% of that immediately after suspending when the composition is suspended.
  • the sustained-release composition of the present invention is less toxic and thus can be safely administered to mammals (mouse, rat, dog, cat, sheep, pig, horse, bovine, monkey, human and the like).
  • the dosage of the sustained-release composition of the present invention varies depending on the kind and content of a physiologically active substance, duration of sustained-release of a physiologically active substance, the targeted animal, the purpose of administration, and the like, but may be an effective amount of the physiologically active substance.
  • the dosage can be appropriately selected from the range from about 1 mg to about 10 g, preferably from about 10 mg to about 2 g per time for an adult (body weight 50kg).
  • the volume of the suspension to be administered can be appropriately selected from the range from about 0.1 to about 5 mL, preferably from about 0.5 to about 3 mL.
  • the sustained-release composition of the present invention is effective as an agent for preventing or treating hormone-dependent disease (for example, prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, dysmenorrhea or breast cancer, or the like), a contraceptive agent, an agent for preventing the postoperative recurrence of premenopausal breast cancer, or the like.
  • hormone-dependent disease for example, prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, dysmenorrhea or breast cancer, or the like
  • contraceptive agent for example, an agent for preventing the postoperative recurrence of premenopausal breast cancer, or the like.
  • the monthly dosage of the sustained-release composition for an adult is, for example, about 1.88 to about 15 mg of the physiologically active substance.
  • the sustained-release composition of the present invention is administered to domestic animals (for example, dog, cat, sheep, pig, horse, bovine, monkey and the like) for the purpose of contraception or softening of meat, the dosage is determined by the measured clearance of animals to be administered.
  • the monthly dosage of the sustained-release composition is, for example, about 0.03 to about 3.0 mg/kg of the physiologically active substance.
  • the biodegradable polymer may be replaced by a lactic acid-glycolic acid copolymer in which the weight-average molecular weight (Mw) is about 10,500 to about 14,500, the ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) is 2.3 to 3.1, and the compositional molar ratio of lactic acid to glycolic acid is 99.9/0.1 to 60/40, or a salt thereof, and the resulting sustained-release composition can be used similarly to the sustained-release composition of the present invention.
  • Mw weight-average molecular weight
  • Mn number-average molecular weight
  • the compositional molar ratio of lactic acid to glycolic acid is 99.9/0.1 to 60/40, or a salt thereof
  • the weight-average molecular weight and the number-average molecular weight of the lactic acid-glycolic acid copolymer used can be measured, for example, using the GPC method (1) or the GPC method (2) of Reference Example 1.
  • the weight-average molecular weight (Mw) is preferably about 11,500 to about 14,500 (more preferably about 11,600 to about 14,500). However, specifically, when measured by using the GPC method (1), the weight-average molecular weight (Mw) is preferably about 11,500 to about 14,000 (more preferably about 11,600 to about 14,000). When measured by using the GPC method (2), the weight-average molecular weight (Mw) is preferably about 12,000 to about 14,500.
  • Preferable examples of the ratio of the weight-average molecular weight (Mw) to the number-average molecular weight (Mn) of lactic acid-glycolic acid copolymer, and preferable examples of the compositional molar ratio of lactic acid to glycolic acid are the same as described above.
  • lactic acid-glycolic acid copolymers and the like are preferably used.
  • sustained-release composition examples include sustained-release microcapsules described in Examples A1-A3 and Examples B1-B5, and among them, sustained-release microcapsules described in Examples B1-B5 are preferably used.
  • the sustained-release composition of the present invention can exert the excellent sustained-release property. Furthermore the sustained-release composition of the present invention is effective as an agent for preventing or treating prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, dysmenorrhea or breast cancer, a contraceptive agent, or an agent for preventing the postoperative recurrence of premenopausal breast cancer.
  • the % (percentage) represents % by weight unless it is especially noted.
  • a lactic acid-glycolic acid copolymer comprising 75 mol% of DL-lactic acid and 25 mol% of glycolic acid was used.
  • THF tetrahydrofuran
  • polystyrene standard products F-10, F-2, A-5000 and A-1000 having known molecular weights is weighed, THF is added to dissolve it to 40 mL, and a standard solution A is obtained.
  • polystyrene standard products F-4, F-1, A-2500 and A-500 having known molecular weights is weighed, THF is added to dissolve it to 40 mL, and a standard solution B is obtained.
  • Detector differential refractometer (having performance equivalent to that of HLC-8120 GPC system) Column: TSK guardcolumn H HR -L (40 ⁇ 6.0 mm i.d.) TSKgel G4000H HR (300 ⁇ 7.8 mm i.d.) TSKgel G3000H HR (300 ⁇ 7.8 mm i.d.) TSKgel G2000H HR (300 ⁇ 7.8 mm i.d.) TSKgel G1000H HR (300 ⁇ 7.8 mm i.d.)
  • the separation degree between the peak of F-10 and the peak of F-2 is 2.0 or more, and the theoretical step number and symmetry coefficient of both peaks are 8000 steps or more and 1.5 or less, respectively.
  • the relative standard deviation between retention times of respective peaks is 3.3% or less.
  • Mw of the polystyrene standard products values evaluated by a GPC method are used.
  • Mw of the polystyrene standard products in the case of A-1000 and A-500, values evaluated by a GPC method are used, and in the other cases, values evaluated by a light scattering method are used.
  • leuprorelin acetate content 98.5%
  • 13 g of distilled water for injection was added and leuprorelin acetate was dissolved in a warm bath at 80°C to prepare an A solution.
  • microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan). The microcapsules were dispersed again in distilled water for injection. To the dispersion, 18 g (18.0 g) of mannitol as an aggregation prevention agent was added and dissolved. The dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 8.3% of leuprorelin acetate, and was in a spherical shape. It was found that the obtained microcapsule powder continuously released leuprorelin acetate over one month by an animal test (rat).
  • microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan). The microcapsules were dispersed again in distilled water for injection. To the dispersion, 18g of mannitol as an aggregation prevention agent was added and dissolved. The dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 8.2% of leuprorelin acetate, and was in a spherical shape. It was found that the obtained microcapsule powder continuously released leuprorelin acetate over one month by an animal test (rat).
  • leuprorelin acetate content 98.5%
  • 13 g of distilled water for injection was added and leuprorelin acetate was dissolved in a warm bath at 80°C to prepare an A solution.
  • microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan). The microcapsules were dispersed again in distilled water for injection. To the dispersion, 18g of mannitol as an aggregation prevention agent was added and dissolved. The dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 8.2% of leuprorelin acetate, and was in a spherical shape. It was found that the obtained microcapsule powder continuously released leuprorelin acetate over one month by an animal test (rat).
  • this W/O emulsion was cooled to about 19°C, it was poured into 200 L of a 0.1% (w/w) polyvinyl alcohol aqueous solution (EG-40, made by Nippon Synthetic Chemical Industry Co., Ltd.) which had been previously adjusted to about 19°C.
  • the mixture was emulsified by stirring at about 7000 rpm using HOMOMIC LINE FLOW (manufactured by Tokushukika) to prepare a W/O/W emulsion.
  • This W/O/W emulsion was stirred at about 2500 rpm for 3 hours to volatilize or diffuse dichloromethane into the outer aqueous phase and to solidify the oil phase.
  • microcapsules After passed through a sieve having an opening of 75 ⁇ m, microcapsules were continuously settled with a centrifuge separator at about 2000 rpm and then collected. The collected microcapsules were dispersed into a small amount of distilled water and then passed through a sieve having an opening of 90 ⁇ m. Thereto 174.5 g of mannitol was added and dissolved. This was lyophilized to prepare microcapsule powder containing leuprorelin acetate. The microcapsule powder contained 8.5% of leuprorelin acetate.
  • leuprorelin acetate content 96.9%
  • leuprorelin acetate content 96.9%
  • leuprorelin acetate was dissolved in a warm bath at 80°C to prepare an A solution.
  • the viscosity of the sample was 1050 cp.
  • 2.5 L of the C solution was diluted with distilled water for injection to 25 L and then adjusted to 18°C.
  • Thereto the above-described W/O emulsion was added.
  • the mixture was emulsified at 7,000 rpm with a propeller-type stirrer (Homomic line flow/100-type, Tokushukika Kogyo Co., Ltd.) to prepare a W/O/W emulsion.
  • methylene chloride was removed by in-water drying method.
  • microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan). The microcapsules were dispersed again in distilled water for injection. To the dispersion, 17 g of mannitol as an aggregation prevention agent was added and dissolved. The dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 8.6% of leuprorelin acetate, and was in a spherical shape. It was found that the obtained microcapsule powder continuously released leuprorelin acetate over one month by an animal test (rat).
  • leuprorelin acetate content 96.9%
  • leuprorelin acetate content 96.9%
  • leuprorelin acetate was dissolved in a warm bath at 80°C to prepare an A solution.
  • the viscosity of the sample was 1300 cp.
  • 2.5 L of the C solution was diluted with distilled water for injection to 25 L and then adjusted to 18°C.
  • Thereto the above-described W/O emulsion was added.
  • the mixture was emulsified at 7,000 rpm with a propeller-type stirrer (Homomic line flow/100-type, Tokushukika Kogyo Co., Ltd.) to prepare a W/O/W emulsion.
  • methylene chloride was removed by in-water drying method.
  • microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan). The microcapsules were dispersed again in distilled water for injection. To the dispersion, 17 g of mannitol as an aggregation prevention agent was added and dissolved. The dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 8.8% of leuprorelin acetate, and was in a spherical shape. It was found that the obtained microcapsule powder continuously released leuprorelin acetate over one month by an animal test (rat).
  • leuprorelin acetate content 96.3%
  • leuprorelin acetate content 96.3%
  • leuprorelin acetate was dissolved in a warm bath at 80°C to prepare an A solution.
  • the viscosity of the sample was 1990 cp.
  • 2.5 L of the C solution was diluted with distilled water for injection to 25 L and then adjusted to 18°C.
  • Thereto the above-described W/O emulsion was added.
  • the mixture was emulsified at 7,000 rpm with a propeller-type stirrer (Homomic line flow/100-type, Tokushukika Kogyo Co., Ltd.) to prepare a W/O/W emulsion.
  • methylene chloride was removed by in-water drying method.
  • microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan). The microcapsules were dispersed again in distilled water for injection. To the dispersion, 17 g of mannitol as an aggregation prevention agent was added and dissolved. The dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 8.6% of leuprorelin acetate, and was in a spherical shape. It was found that the obtained microcapsule powder continuously released leuprorelin acetate over one month by an animal test (rat).
  • leuprorelin acetate content 96.3%
  • leuprorelin acetate content 96.3%
  • leuprorelin acetate was dissolved in a warm bath at 80°C to prepare an A solution.
  • the viscosity of the sample was 1670 cp.
  • 2.5 L of the C solution was diluted with distilled water for injection to 25 L and then adjusted to 18°C.
  • Thereto the above-described W/O emulsion was added.
  • the mixture was emulsified at 7,000 rpm with a propeller-type stirrer (Homomic line flow/100-type, Tokushukika Kogyo Co., Ltd.) to prepare a W/O/W emulsion.
  • methylene chloride was removed by in-water drying method.
  • microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan). The microcapsules were dispersed again in distilled water for injection. To the dispersion, 17 g of mannitol as an aggregation prevention agent was added and dissolved. The dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 8.7% of leuprorelin acetate, and was in a spherical shape. It was found that the obtained microcapsule powder continuously released leuprorelin acetate over one month by an animal test (rat).
  • leuprorelin acetate content 97.2%
  • leuprorelin acetate content 97.2%
  • leuprorelin acetate was dissolved in a warm bath at 80°C to prepare an A solution.
  • the rough emulsion was emulsified at 10,000 rpm for 1 minute twice with a propeller-type stirrer (Autohomomixer/M-type, Tokushukika Kogyo Co., Ltd.) to prepare a W/O emulsion.
  • a propeller-type stirrer Autohomomixer/M-type, Tokushukika Kogyo Co., Ltd.
  • the liquid temperature of the W/O emulsion was 31.4°C.
  • the W/O emulsion was cooled to 19°C, and the viscosity was adjusted.
  • the viscosity was 1450 cp (19.6°C), as measured with a vibration viscometer (VM-100, Yamaichi Electronics Co., Ltd.). 25 L of a 0.1% (w/v) polyvinyl alcohol aqueous solution was adjusted to 18°C. Thereto the above-described W/O emulsion was added. The mixture was emulsified at 7,000 rpm with a propeller-type stirrer (Homomic line flow/100-type, Tokushukika Kogyo Co., Ltd.) to prepare a W/O/W emulsion. After the above-described W/O/W emulsion was stirred for 3 hours, methylene chloride was removed by in-water drying method. After microcapsules with large particle diameter were filtered off through a 75 ⁇ m sieve, microcapsules were collected at 2,000 rpm by a successional centrifuge separator (H-600S / made by Kokusan).
  • microcapsules were dispersed again in distilled water for injection.
  • 16 g of mannitol as an aggregation prevention agent was added and dissolved.
  • the dispersion thus obtained was lyophilized to prepare microcapsule powder containing leuprorelin acetate.
  • Mannitol was used in such an amount that the microcapsule powder contained about 15% of mannitol.
  • the obtained microcapsule powder contained 9.0% of leuprorelin acetate, had a leuprorelin acetate-trapping rate of 94.7%, and was in a spherical shape.
  • the sustained-release composition of the present invention is effective as an agent for preventing or treating prostate cancer, prostatomegaly, endometriosis, hysteromyoma, metrofibroma, precocious puberty, dysmenorrhea or breast cancer, a contraceptive agent, or an agent for preventing the postoperative recurrence of premenopausal breast cancer.

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Claims (18)

  1. Composition à libération prolongée qui comprend (i) une substance physiologiquement active et (ii) un copolymère d'acide lactique-acide glycolique ayant un poids moléculaire moyen en poids (Mw) d'environ 8000 à environ 11 500, un rapport du poids moléculaire moyen en poids (Mw) au poids moléculaire moyen en nombre (Mn) de 2,3 à 3,1, et un rapport molaire compositionnel de l'acide lactique à l'acide glycolique de 99,9/0,1 à 60/40, ou un sel de celui-ci, et qui ne comprend pas de substance retenant au médicament.
  2. Composition à libération prolongée selon la revendication 1, qui est produite par mélange (i) d'une solution contenant une substance physiologiquement active et ne comprenant pas de substance retenant au médicament et (ii) d'une solution ajustée à environ 25 à environ 35 °C et contenant un copolymère d'acide lactique-acide glycolique ayant un poids moléculaire moyen en poids (Mw) d'environ 8000 à environ 11 500, un rapport du poids moléculaire moyen en poids (Mw) au poids moléculaire moyen en nombre (Mn) de 2,3 à 3,1, et un rapport molaire compositionnel de l'acide lactique à l'acide glycolique de 99,9/0,1 à 60/40, ou un sel de celui-ci pour préparer une émulsion eau dans l'huile d'environ 25 à environ 35 °C ; refroidissement de l'émulsion eau dans l'huile à environ 15 à environ 20 °C ; dispersion de l'émulsion eau dans l'huile dans une phase aqueuse pour préparer une émulsion eau dans l'huile dans l'eau ; puis soumission de l'émulsion eau dans l'huile dans l'eau à un séchage dans l'eau.
  3. Composition à libération prolongée selon la revendication 1, dans laquelle la substance physiologiquement active est un dérivé de LH-RH.
  4. Composition à libération prolongée selon la revendication 1, dans laquelle la substance physiologiquement active est un peptide représenté par la formule :

            5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z

    dans laquelle Y est DLeu, DAla, DTrp, DSer (tBu), D2Nal ou DHis (ImBzl), et Z représente NH-C2H5 ou Gly-NH2,
    ou un sel de celui-ci.
  5. Composition à libération prolongée selon la revendication 1, dans laquelle la substance physiologiquement active est un peptide représenté par 1a formule :

            5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C2H5

    ou l'acétate de celui-ci.
  6. Composition à libération prolongée selon la revendication 1, dans laquelle la substance physiologiquement active est présente à environ 5 % en poids à environ 24 % en poids.
  7. Composition à libération prolongée selon la revendication 1, qui est une microcapsule à libération prolongée.
  8. Procédé de production d'une composition à libération prolongée selon la revendication 1, qui comprend le mélange (i) d'une solution contenant une substance physiologiquement active et ne comprenant pas de substance retenant au médicament et (ii) d'une solution ajustée à environ 25 à environ 35 °C et contenant un copolymère d'acide lactique-acide glycolique ayant un poids moléculaire moyen en poids (Mw) d'environ 8000 à environ 11 500, un rapport du poids moléculaire moyen en poids (Mw) au poids moléculaire moyen en nombre (Mn) de 2,3 à 3,1, et un rapport molaire compositionnel de l'acide lactique à l'acide glycolique de 99,9/0,1 à 60/40, ou un sel de celui-ci pour préparer une émulsion eau d'ans l'huile d'environ 25 à environ 35 °C ; le refroidissement de l'émulsion eau dans l'huile à environ 15 à environ 20 °C ; la dispersion de l'émulsion eau dans l'huile dans une phase aqueuse pour préparer une émulsion eau dans l'huile dans l'eau ; puis la soumission de l'émulsion eau dans l'huile dans l'eau à un séchage dans l'eau.
  9. Composition pharmaceutique qui comprend la composition à libération prolongée selon la revendication 1.
  10. Agent qui comprend la composition à libération prolongée selon la revendication 3, pour une utilisation dans la prévention ou le traitement du cancer de la prostate, de la prostatomégalie, de l'endométriose, du myome utérin, du métrofibrome, de la puberté précoce, de la dysménorrhée ou du cancer du sein, ou en tant qu'agent contraceptif.
  11. Agent qui comprend la composition à libération prolongée selon la revendication 3, pour une utilisation dans la prévention de la récurrence postopératoire du cancer du sein préménopausique.
  12. Utilisation d'une composition à libération prolongée comprenant (i) un dérivé de LH-RH et (ii) un copolymère d'acide lactique-acide glycolique ayant un poids moléculaire moyen en poids (Mw) d'environ 8000 à environ 11 500, un rapport du poids moléculaire moyen en poids (Mw) au poids moléculaire moyen en nombre (Mn) de 2,3 à 3,1, et un rapport molaire compositionnel de l'acide lactique à l'acide glycolique de 99,9/0,1 à 60/40, ou un sel de celui-ci, et ne contenant pas de substance retenant au médicament pour la fabrication d'un médicament destiné à prévenir ou traiter le cancer de la prostate, la prostatomégalie, l'endométriose, le myome utérin, le métrofibrome, la puberté précoce, la dysménorrhée ou le cancer du sein, ou d'un agent contraceptif.
  13. Utilisation d'une composition à libération prolongée comprenant (i) un dérivé de LH-RH et (ii) un copolymère d'acide lactique-acide glycolique ayant un poids moléculaire moyen en poids (Mw) d'environ 8000 à environ 11 500, un rapport du poids moléculaire moyen en poids (Mw) au poids moléculaire moyen en nombre (Mn) de 2,3 à 3,1, et un rapport molaire compositionnel de l'acide lactique à l'acide glycolique de 99,9/0,1 à 60/40, ou un sel de celui-ci, et ne contenant pas de substance retenant au médicament pour la fabrication d'un médicament destiné à prévenir récurrence postopératoire du cancer du sein préménopausique.
  14. Utilisation selon la revendication 12 ou 13, dans laquelle la composition à libération prolongée est produite par mélange (i) d'une solution contenant un dérivé de LH-RH et ne comprenant pas de substance retenant au médicament et (ii) d'une solution ajustée à environ 25 à environ 35 °C et contenant un copolymère d'acide lactique-acide glycolique ayant un poids moléculaire moyen en poids (Mw) d'environ 8000 à environ 11 500, un rapport du poids moléculaire moyen en poids (Mw) au poids moléculaire moyen en nombre (Mn) de 2,3 à 3,1, et un rapport molaire compositionnel de l'acide lactique à l'acide glycolique de 99,9/0,1 à 60/40, ou un sel de celui-ci pour préparer une émulsion eau d'ans l'huile d'environ 25 à environ 35 °C ; refroidissement de l'émulsion eau dans l'huile à environ 15 à environ 20 °C ; dispersion de l'émulsion eau dans l'huile dans une phase aqueuse pour préparer une émulsion eau dans l'huile dans l'eau ; puis soumission de l'émulsion eau dans l'huile dans l'eau à un séchage dans l'eau.
  15. Utilisation selon la revendication 12 ou 13, dans laquelle le dérivé de LH-RH est un peptide représenté par la formule :

            5-oxo-Pro-His-Trp-Ser-Tyr-Y-Leu-Arg-Pro-Z

    dans laquelle Y est DLeu, DAla, DTrp, DSer (tBu), D2Nal ou DHis (ImBzl), et Z représente NH-C2H5 ou Gly-NH2,
    ou un sel de celui-ci.
  16. Utilisation selon la revendication 12 ou 13, dans laquelle le dérivé de LH-RH est un peptide représenté par la formule :

            5-oxo-Pro-His-Trp-Ser-Tyr-DLeu-Leu-Arg-Pro-NH-C2H5

    ou l'acétate de celui-ci.
  17. Utilisation selon la revendication 12 ou 13, dans laquelle le dérivé de LH-RH est présent à environ 5 % en poids à environ 24 % en poids.
  18. Utilisation selon la revendication 12 ou 13, dans laquelle la composition à libération prolongée est une microcapsule à libération prolongée.
EP05758111.8A 2004-07-02 2005-06-30 Une procédure pour produire les microcapsules à libération prolongée Active EP1765295B2 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
JP2004196831 2004-07-02
JP2004267537 2004-09-14
JP2004296635 2004-10-08
JP2005023261 2005-01-31
PCT/JP2005/012517 WO2006004167A1 (fr) 2004-07-02 2005-06-30 Composition à libération prolongée, procédé servant à produire celle-ci et utilisation de celle-ci

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EP1765295A1 EP1765295A1 (fr) 2007-03-28
EP1765295B1 true EP1765295B1 (fr) 2012-09-12
EP1765295B2 EP1765295B2 (fr) 2015-09-09

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EP (1) EP1765295B2 (fr)
JP (1) JP5601749B2 (fr)
CA (1) CA2571583C (fr)
ES (1) ES2391460T5 (fr)
TW (1) TW200613012A (fr)
WO (1) WO2006004167A1 (fr)

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CA2571583A1 (fr) 2006-01-12
JP5601749B2 (ja) 2014-10-08
JP2008505057A (ja) 2008-02-21
TW200613012A (en) 2006-05-01
ES2391460T3 (es) 2012-11-27
ES2391460T5 (es) 2015-10-27
US20080118545A1 (en) 2008-05-22
EP1765295B2 (fr) 2015-09-09
EP1765295A1 (fr) 2007-03-28
CA2571583C (fr) 2013-04-30
WO2006004167A1 (fr) 2006-01-12

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